DESCRIPTION: Ocular immune privilege enables the eye to respond to antigenic challenges in ways that preserve the delicate structures of the eye. Although we and others have found active and passive mechanisms of immune privilege to retinal antigens, the details are not yet clear. Passive mechanisms produce immunological ignorance, the functional absence of interactions between the immune system and retinal antigens. In part, immunological ignorance is due to sequestration resulting from the blood/retinal barrier, which reduces lymphocytic perusal of the retina, minimizes leakage of antigens, and limits conventional lymphatic drainage. Based on our recent results, we propose that the lack of local antigen presenting cells is an important complementary mechanism of immunological ignorance closely associated with sequestration. Since it is clear that activated T cells access the retinal Parenchyma in spite of the barriers, limiting the antigen presenting cells would further constrain potential encounters with antigen, thus reducing potential inflammation and damage. In this respect, it appears that the retina differs from other CNS tissue, which is well-endowed with antigen presenting cells. Previous studies concentrated on CD4 T cells, their MHC class II-restricted responses, and the pathogenesis of CD4 T cell mediated responses to retinal antigens. The antigen presenting cells that were the focus of those studies were the microglia and perivascular cells - retinal cells capable of expressing MHC class II. In contrast, Aim I of this proposal examines the mechanism of the near-surgical, precision killing of retinal neurons, long thought to be MHC class I-negative, by CD8 T cells. This observation raises fundamental questions regarding the mechanisms by which class I-restricted T cells eliminate cells that appear to be class I negative, and express the target antigen intracellularly. Curiously, antigen-negative, MHC class I-negative neurons in the cerebellum (granule cells) are also killed. Our approach is based on mice with transgenic expression of the target antigen beta-galactosidase in either neurons (photoreceptor cells) or microglia (astrocytes, MHC class I-positive), enabling this critical distinction to be tested. Aim II examines the possibility that local antigen presenting cells are limiting, in number and/or function, thus contributing to retinal immune ignorance and privilege.